Download P-Nuclear magnetic resonance evidence of abnormal

Eur Resplr J
1992, 5, 163-189
31
P-Nuclear magnetic resonance evidence of abnormal
skeletal muscle metabolism in patients with chronic lung
disease and congestive heart failure
H. Tada, H. Kato, T. Misawa, F. Sasaki, S. Hayashi,
H. Takahashi, Y. Kutsumi, T. lshizaki, T. Nakai, S. Miyabo
31
P-Nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism
in patients with chronic lung disease and congestive heart failure. H. Tada, H. Kato,
T. Misawa, F. Sasaki, S. Hayashi, H. Takahashi, Y Kutsumi, T. Ishizaki, T. Nakai,
S. Miyabo.
ABSTRACT: The development of 31 P·nuclear magnetic resonance (NMR) has
enabled direct and non·lnvaslve measurements of muscle metabolism. Serial
measurements of the phosphocreatine/inorganic phosphate (PCr!Pl) ratio, which
is closely related to the adenosine triphosphate/adenosine diphosphate (ATP/
ADP) ratio and pH during and after forearm exercise were performed in 11
patients with chronic lung disease (CLD), nine patients with chronic heart
failure (CHF) and eight control subjects. As compared with control subjects,
the PCr/Pi ratio in the patients with CLD or CHF was lower during the
recovery period and significantly lower at three and 4 mln exercise. The pH
values after exercise were lower in patients with CLD or CHF compared to
control subjects.
The PCr/Pi ratio at 4 mln after exercise In the patients with CLD or CHF
did not correlate with parameters of cardiac function or arterial and mixed
venous oxygen tension. The arterial oxygen content and output in patients with
CLD and CHF were significantly lower than that of control subjects.
Nutritional parameters were not statistically different among the three groups.
These observations suggest that metabolic abnormalities may be present In
the skeletal muscles of patients with CLD and CHF that are not due to under·
nutrition. These may result from reduced arterial oxygen output and, partially,
from physical detraining.
Eur Respir J, 1992, 5, 163-169.
Patients with chronic lung disease (CLD) or chronic
heart failure (CHF) are forced to limit daily exercise.
Numerous reports have found poor correlations
between exercise tolerance and measurements of
pulmonary and cardiac function [1, 2]. Intrinsic
muscle abnormality may play an important role in
exercise capacity of patients with CHF [3]. It has
been reported that intrinsic muscle abnormality might
result from the effects of exercise deconditioning and
undernutrition [4-6). A number of studies have
investigated correlations between exercise tolerance
and indices of cardiopulmonary function in patients
with CLD [7), but there have been no reports focusing on the role of peripheral factors as determinants
of exercise limitation.
Skeletal muscle metabolism has been studied with
the use of either venous blood samples or muscle
biopsy specimens. The development of 31P-nuclear
magnetic resonance (NMR) has enabled direct and
non-invasive measurements of muscle metabolism at
Third Department of Internal Medicine
Fukui Medical School
Fukui
Iapao.
Correspondence: T. Ishizaki
Third Department of Internal Medicine
Fukui Medical School
23 Shimoaizuki, Matsuoka-Cho
Fukui 910·11
Japan.
Keywords: Chronic heart failure
chronic lung disease;
31 P-nuclear magnetic resonance
skeletal muscle.
Received: April 16, 1991; accepted
after revision October 23, 1991.
rest and during different forms of exercise metabolic
changes being assessed by measurement of high-energy
phosphates and intracellular pH. A number of
studies have suggested that alterations in muscle
metabolism may represent one of many factors that
explain the marked heterogeneity of symptoms and
exercise intolerance of patients with CHF [8, 9).
The purpose of the present study was to investigate
skeletal muscle metabolism during exercise in patients
with CLD and CHF and the relationship of metabolic
variables to cardiac haemodynamics.
Methods
Subjects
Eleven male patients with stable CLD were studied;
mean age 69±6 yrs (±so). The cause of CLD was
chronic obstructive pulmonary disease (COPD) in
H. TADA ET AL.
164
seven patients and restrictive pulmonary disease
(old pulmonary tuberculosis) in four patients. The duration of CLD ranged from 2-23 yrs. The degree of
dyspnoea in patients 2, 3, 5 and 1 was Hugh-Jones
class 11, Ill, IV and V, respectively. For comparison,
a group of eight age-matched (65±7.1 yrs) sedentary
male control subjects (control) and nine age-matched
(62±6.8 yrs) male patients with CHF were studied.
The degree of heart failure in patients 5, 3 and 1 was
functional class 11, Ill and IV (New York Heart Association), respectively. Control subjects complained
of anterior chest discomfort and were admitted for the
purpose of cardiac catheterization. They showed no
cardiopulmonary abnormalities on physical examination, chest X-p, spirometry, electrocardiogram or twodimensional echocardiography, but exercise-loaded
electrocardiogram revealed mild ST-T abnormality, although not clearly significant, and all of them had no
significant stenosis of the coronary arteries.
All CLD patients complained of dyspnoea, the
degree of which was more than could be expected
from chest X-p, spirometry and arterial blood gas
analysis. Therefore, Swan-Ganz catheterization was
performed, and the effects of some vaso-active agents
(0 2, nitrates, Ca 2+ blocker) on the cardiopulmonary
system were investigated. Patients with CLD had no
history of cardiac disease or abnormalities. Patients
with CHF had no history of pulmonary disease or
abnormalities. Mter cardiac catheterization, all of the
subjects were thoroughly informed of the aims of the
research and gave their consent.
Exercise protocol
Mter positioning the forearm within the magnet, a
3 min resting NMR spectrum was obtained. The
exercise routine consisted of repetitive finger flexor
pulling of a lever with the three distal phalanges at a
rate of 60·min' 1 (fig. 1). The lever was attached
through a pulley system to a mass that was lifted a
fixed distance of 0.05 m with each repetition. Exercise was commenced with an initial weight of 1.0 kg,
which was maintained for 2 min, then with a weight
of 1.25 kg, which was maintained for another 2 min.
The total work was 132.3 J ( = mass (1 kg or 1.25 kg)
x force of gravity (9.8 m·s·2) x distance (0.05 m) x
60 (times·min· 1) x 4 min). The work rate during the
initial 2 min of exercise and during the last 2 min of
exercise was 0.49 J per repetition (at repetition per
1 s; average power output, 0.49 W) and 0.61 J per
repetition (at repetition per 1 s; average output, 0.61
W), respectively.
Magnetic field
2.0 t MRS (BEM 250/80)
Nuclear magnetic resonance procedure
NMR spectroscopy was performed with a 2.0 tesla,
30 cm bore superconducting magnet interfaced with
a spectrometer operating at frequencies of 35.3 and
87.1 MHz for 31P and 1H, respectively, (BEM 250/80,
Otsuka Electric, Osaka, Japan). The subject sat beside the magnet positioned so that the flexor digitorum
superficialis muscle of the dominant arm rested on a
coil with a surface diameter of 2.0 cm. The magnetic
field was adjusted for homogeneity so that the line
width at half maximum of the water proton was < 40
Hz. 31 P spectra were obtained with the use of a 30
degree excitation pulse with a 2 s repetition rate.
Sixty free-induction decays were summed for each
measurement. NMR spectroscopy was performed at
rest (Pre), during exercise (E1_) and recovery (R 1_).
Exercise and recovery scans were recorded every minute for 4 min. To assess the changes in intracellular
pH, we determined the chemical shift of the pHdependent inorganic phosphate (Pi) peak ( ao) relative
to the pH-independent phosphocreatine (PCr) peak.
Intracellular pH was calculated from the chemical shift
data and Pi titration curve by the following equation
[10]:
pH = pK -log10 (ao - aB)!(aA - ao)
where oA=3.290, oB=S.BOS, and pK=6.90.
I
Load
1-1.25 kg
Fig. 1. - Schematic representation of the exercise system used in
the present study. MRS: magnetic resonance spectroscopy The
exercise routine consisted of repetitive finger flexor pulling a lever
with the three distal phalanges at a rate of 60·min· 1• The lever was
attached through a pulley system to a mass that was lifted a fixed
distance of 0.05 m with each repetition.
Spectra analysis
Quantification of metabolic components was
obtained from the Fourier-transformed NMR spectra
signal-amplitude analysis. PCr and Pi peak levels
were measured and used to calculate the PCr/Pi ratio.
Examination of cardiopulmonary functions
Spirometry, blood gas measurements and Swan-Ganz
catheterization were performed on all subjects. The
SKELETAL MUSCLE METABOLISM IN CHRONIC LUNG DISEASE
evaluations included forced expiratory volume in
one second (FEV 1), the FEY-forced vital capacity
ratio (FEV1 %), forced vital capacity (FVC), arterial
and mixed venous (pulmonary arterial) carbon dioxide
tension (Paco2 and Pvcoz), oxygen tension (Pao2 and
Pvo ), pH (pHa and pHv), heart rate (HR), mean
7
aortlc pressure (AoPmean), mean pulmonary pressure
(PAPmean), mean pulmonary capillary wedge pressure
(PCWPmean), mean right atrial pressure (RAPmean),
cardiac index (Cl), arterial oxygen content (Cao 2 ;
Cao 2 =Hb x 0.0134 x arterial oxygen saturation
(Sao~ + Pao 2 x 0.003), and arterial oxygen output
(AOU; AOO = cardiac output x Caoz). Mean left ventricular ejection fractions (EF) were measured by
either two-dimensional echocardiography or radionuclide angiography. All above mentioned examinations were accomplished within three days prior to
NMR study.
165
PCr
-5,000
5,000
15,000
25,000
35,000
Frequency in ppm
(b)
13-ATP
R4
R3
R2
R1
E4
E3
E2
Nutritional and metabolic parameters
Body mass index (kg·m· 2) was calculated from
body weight (kg) divided by height 2 (m 2). Triceps
skinfold thickness was measured with Lange skinfold
calipers. Arm muscle circumference and creatinine
height indices were calculated according to the methods of BLACKBURN and HARVEY [11]. We measured
maximal grasp power and forearm muscle circumference (FMC) in the region where the surface coil was
placed. FMC was calculated from the forearm circumference (FC) and skinfold (FSF) in the region where
the surface coil was placed (FMC (cm)= FC (cm)(0.314 x FSF(mm)).
Serum chemistries obtained routinely at initial evaluation included magnesium, creatinine, albumin, total
cholesterol, haematocrit, leucocyte count, absolute
lymphocyte count and iron.
E1
Pre
-5,000
5,000
15,000
25,000
35,000
25,000
35,000
Frequency in ppm
PCr
Statistical analysis
All data were expressed as the mean:t:so. Statistical analysis was done by one-way analysis of variance
(ANOVA) with the Bonferroni simultaneous multiple
comparison method to test the significance of the
differences among the means in the three groups. Statistical analysis of the PCr/Pi ratio and pH was initially analysed using two-way ANOVA. When group
differences were found, one-way ANOVA with the
Bonferroni simultaneous multiple comparison method
was used. A probability of <5% was considered significant.
Results
Forearm energy metabolism
Figure 2 shows representative spectra of 31 P-NMR
obtained from the control, CLD and CHF groups at
rest (Pre ), during exercise (E 1_) and recovery (R 1_) •
-5,000
5,000
15,000
Frequency in ppm
Fig. 2. - Representative spectra of 31 P-NMR obtained at rest
(Pre), during exercise (E1_.), and recovery (R 1_.) from the control
(a), chronic lung disease (b) and chronic heart failure (c) groups.
Pi: inorganic phosphate; PCr: phosphocreatine; ATP: adenosine
triphosphate; ppm: parts per million; NMR: nuclear magnetic
resonance.
Phosphocreatine (PCr) and inorganic phosphate (Pi)
level in the control, CLD and CHF group did not significantly differ under rest conditions (control vs CLD
vs CHF: Pi: 62.8:t:28.3 vs 58.4:t:21.5 vs 60.6:t:19.9; PCr:
405.5:t:136.2 vs 351.4:t:l18.9 vs 381.3:t:170.8; PCr/Pi:
5.81:t:2.03 vs 6.52±2.88 vs 5.91:t:2.48). The values
indicate integrated areas for that peak in absolute
units.
H. TADA ET AL.
166
Exercise induced a progressive decrease in PCr and
an increase in Pi. PCr and Pi tended to recover after
terminating exercise in all three groups. Figure 3
shows the changes in PCr/Pi during exercise and during recovery. In the CLD and CHF groups, there was
a tendency for the PCr/Pi ratio during exercise to be
lower than the control group, but there were no
statistical differences. Furthermore, the PCr/Pi ratio in
the CLD and CHF groups poorly recovered to the
pre-exercise levels at three (R 3) and four (R4) minutes
after exercise, a significantly lower value than that
of the control group (p<0.05 or p<0.001).
the CLD and CHD groups, without significant difference from the control group. The pH at 4 min
after exercise (E 4) in the control, CLD and CHF
groups was 6.91±0.44, 6.61±0.18 and 6.58±0.30,
respectively.
The relationship between the PCr/Pi ratio at 4 min
after exercise and several variables
We investigated the relationship between the PCr/Pi
ratio at 4 min after exercise and several variables
180
160
140
0:::
-.:::.
(.) 120
a..
.~
100
Cl)
C)
a
..c:
(.)
*'
80
60
40
20
0
Pre
Fig. 3. -
E,
E2
E3
E4
R,
R2
R3
R4
The changes in the PCr/Pi ratio at rest (Pre), during exercise (E1_.) and recovery
(Rl_.). Values are mean:tso. Control: control subjects (D); CHF: patients with chronic heart
fai ure ( r.d); CLD: patients with chronic lung disease (.). •: p<O.OS compared with control.
t: p<O.OOl compared with control. PCr: phosphocreatine; Pi: inorganic phosphate.
7.4
7.2
7.0
:I:
a. 6.8
6.6
6.4
6.2
6.0
Pre
E,
E2
E3
E4
R,
R2
R3
R4
Fig. 4. - The changes in pH at rest (Pre), during exercise (E1_.) and recovery (R 1_.).
Values are meauso. Control subjects ( --o- ); CHF: patients with chronic heart failure
( --&-- ); CLD: patients with chronic lung disease (- • -).
Figure 4 shows the changes in pH during exercise
and recovery. The pH at rest and during exercise
were similar in all three groups. However, recovery
of pH after terminating exercise was delayed in
(PAPmean, RAPmean, PCWPmean, Pao.l, Pvo2, EF,
Cl, Cao2 and AOO); in the CLD and CHF groups;
there were no significant correlation (data not
shown).
SKELETAL MUSCLE METABOLISM IN CHRONIC LUNG DISEASE
Steady-state pulmonary function, blood gases and
haemodynamic data
Table 1 shows steady-state pulmonary function,
blood gases and haemodynamic data. In the CLD
group, FEV1, FEV 1% and FVC were significantly
lower than those in the other groups. Furthermore, in
the CLD group Pao 2 was significantly lower and Paco2
higher compared to both control and CHF groups.
Pvo2 was slightly lower in the CHF and CLD groups,
but there was no statistical difference among the three
groups. Arterial blood gas data measured before and
just after forearm exercise in a few of the patients with
CLD were similar (data not shown).
Table 1. - Steady-state lung function, blood gases,
and haemodynamic data
Control
CHF
FVC % pred
2.47:t0.73
75.0±9.1
3.33±0.94
100.8±26.1
2.26:t0.21
75.4±2.0
3.07±0.33
79.7±28.4
0.87:t0.27t+
50.0±21.7t+
1.99:t0.74t•
62.9:t28.4t
Blood gas
pHa
Pao2 mmHg
kPa
Paco 2 mmHg
kPa
pHv
Pvo2 mmHg
Pvco2 mmHg
7.41±0.04
89.3±11.5
(11.9:t1.5)
36.4±3.4
(4.9±0.5)
7.38±0.02
38.7±2.7
40.8:t3.7
7.42±0.02
89.5±3.6
(11.9:t0.5)
35.3:t5.3
(4.7±0.7)
7.39±0.03
37.3:t2.4
40.5:t5.0
7.40±0.03
67.8±8.4t+
(9.1±1.1)
45.5±5.7t+
(6.1±0.8)
7.38±0.03
36.8±2.9
49.3±8.76
Haemodynamics
HR beats·min·1
AoPmean mmHg
PAPmean mmHg
PCWPmean mmHg
RAPmean mmHg
Cl l·min·1·m2
EF %
Cao vol %
A06 vol %·l·min·1
65.3±8.7
90.3±6.8
14.0±2.1
7.4±3.2
4.9±2.0
3.36±0.59
77.5±8.5
18.0±0.9
99.2±19.9
64.7±8.8
84.9:t8.5
18.4±5.7
12.3±5.1•
8.3±4.1
2.83:t0.52
55.3±24.4•
15.9:t2.1•
71.3:t12.8•
74.5±10.4
91.0±13.6
20.5±2.5t
8.5±2.8
6.9±2.4
3.18±0.66
69.8±11.5
16.0±1.6t
72.6±18.7t
Lung function
FEV1 l
FEV1 %
FVCl
CLD
Values are mean±so. •: significant difference between
control and CHF; t: significant difference between control
and CLD; •: significant difference between CHF and CLD.
FEV1: forced expiratory volume in one second; FVC:
forced vital capacity; % pred: percentage predicted; pHa:
arterial pH; Pao2 : and Paco2 : arterial oxygen and carbon
dioxide tension, respectively; pHv: mixed venous pH; Pvo2
and Pvco 2 : mixed venous oxygen and carbon dioxide tension, respectively; HR: heart rate; AoP: aortic pressure;
PAP: pulmonary artery pressure; PCWP: pulmonary
capillary wedge pressure; RAP: right arterial pressure; Cl:
cardiac index; EF: ejection fraction; Cao 2: arterial oxygen
content; AOO: arterial oxygen output; CHF: chronic heart
failure; CLD: chronic lung disease.
The HR and AoPmean were similar among the three
groups. The PAPmean was slightly higher in the
CHF and CLD group, and in the CLD group it was
significantly higher than that in the control group. The
167
mean value of EF in the CHF group was significantly
lower than it was in the other two groups. The Cao2
in the CLD and CHF group was significantly lower
than that in the control group (p<0.05). The AOO in
the CLD and CHF group was also significantly lower
than that in the control group (p<0.01).
Nutritional and metabolic parameters
Body mass index, creatinine height index, triceps
skinfold and arm muscle circumference did not differ
significantly among the three groups (data not shown).
Other variables (magnesium, creatinine, total protein,
albumin, total cholesterol, haematocrit, white blood cell
count, absolute lymphocyte count and iron) also did
not differ significantly among the three groups (data
not shown). The maximal grasp power in the control,
CHF and CLD groups was 38.2:4.5, 36.5:5.7 and
36 .2:6.0 kg, respectively, showing no significant
differences among the three groups. The FMC in the
control, CHF and CLD groups was 21.2:1.8, 22.7:2.5
and 20.4:1.5 cm, respectively, showing no significant
differences among the three groups.
Discussion
The results of the present study demonstrated that
skeletal muscle metabolism during exercise, as
assessed by 31 P-NMR, is abnormal in patients with
CLD and CHF. The severity of respiratory failure and
pulmonary hypertension in the patients with CLD in
the present study was relatively mild. Nevertheless,
compared with age-matched control subjects, the
PCr/Pi ratio decreased at a faster rate during exercise
despite performing almost the same amount of external work and its recovery was more delayed. The pH
was lower during the recovery period in the patients
with CLD. The phosphorylation potential is an
important measure of the energy status of the cell and
can be used to determine the adequacy of energy
reserves for vital cell functions. The PCr/Pi ratio is
thought to be closely related to the ATP/ADP ratio,
and a reduction of PCr/Pi reflects an impairment in
oxidative metabolism of the muscle [12, 13]. Therefore, we measured the changes in PCr/Pi ratio at rest,
during exercise and during recovery.
Abnormalities of PCr/Pi and pH might be explained
by differences in muscle size. Since NMR samples
a fixed volume of muscle, patients with a reduced
muscle mass performing the same amount of external
work would have greater energy requirements per
gram of muscle examined. While we were unable to
measure muscle mass directly, body mass index,
maximal grasp power, arm muscle circumference and
forearm muscle circumference in the region where
the surface coil was placed were similar in three
groups. Therefore, the differences in skeletal muscle
metabolism cannot be explained by reduced muscle
mass.
168
H. TADA ET AL.
The most plausible explanation for the differences
in muscle metabolism between normal subjects and
patients with CLD and CHD may be reduced blood
flow. Several earlier reports demonstrated that plethysmographic forearm blood flow is reduced in the
patients with CHF [14, 15] at rest and in the supine
position. On the other hand, in the upright or sittingposture forearm blood flow at rest and during
exercise did not show a significant difference between
the control subjects and the patients with CHF [8, 16].
We may have studied patients with less severe
circulatory dysfunction than the subjects studied by
previous investigators; LEITHE et al. [17] showed that
resting forearm blood flow is directly related to the
level of circulatory dysfunction. Following that, metabolic abnormalities observed in the patients with CHF
in the present study cannot be explained by impaired
blood flow. Unfortunately, there are no reports concerning forearm blood flow in patients with CLD.
The patients with CLD in the present study, however,
may have less severe circulatory dysfunction and
we found no remarkable difference in blood flow
between control subjects and patients with CLD.
The fact that abnormal PCr/Pi and pH cannot be
explained by impaired blood flow or muscle atrophy
lets us consider that there is an abnormality of energy
production, or reduced efficiency of contractions in the
CLD and CHF groups examined.
Firstly, an impaired oxygen delivery might be
considered. In our study, the Cao 2 in the CLD and
CHF groups was significantly lower than that in the
control group, and the AOO was also significantly
decreased in both groups. Decreased Cao2 and reduced
cardiac output could give reduced AOO in both
groups, and reduced AOO might reduce efficiency of
contraction and cause abnormal PCr/Pi and pH during
exercise.
Secondly, an abnormality of energy production,
such as reduced mitochondrial oxidative capacity or
altered metabolic control with a metabolic shift toward
dependence on glycolysis might be a mechanism.
This could reflect a change in fibre-type predominance
or in the pattern of fibre recruitment.
Finally, a reduced efficiency of contraction could
necessitate increased adenosine triphosphate (ATP)
hydrolysis. In fact, several reports have demonstrated
that type lib fibre, which was characterized by low
oxidative capacity, fewer mitochondria and easy
fatigue, increased in percentage of composition, and
oxidative enzyme capacity decreased in patients with
CHF [3, 18]. An increased percentage of type lib
fibre is considered to cause reduced PCr/Pi during
exercise and delayed recovery of PCr/Pi after exercise.
Furthermore, alterations found in patients with CHF
are compatible with the effects of exercise deconditioning [4, 5, 19, 20], suggesting that abnormality of
skeletal muscle metabolism might be due to physical
detraining [3, 4, 18). Unfortunately, we could not
examine the alteration in skeletal muscle histology
and biochemistry, and there were no reports concerning altered skeletal muscle in patients with CLD.
However, the patients with CLD and CHF studied in
this study were under more physical detraining
compared to control subjects, and skeletal muscle
metabolism in patients with CLD during exercise, as
assessed by 31P-NMR, was similar to that in patients
with CHF. Therefore, we assume altered skeletal
muscle metabolism in patients with CLD, as well as
in patients with CHF, may be partially due to physical detraining and probably a shift in fibre distribution and a decrease in oxidative capacity.
Malnutrition may also contribute to the abnormalities observed in our patients with CLD and CHF [6].
Skeletal muscle biopsies of severely malnourished
patients have demonstrated extensive necrosis of
muscle fibres, neurogen-like grouping of atrophic type
11 fibres and predominant atrophy of type 11 fibres.
We measured anthropometric parameters and laboratory tests to evaluate the nutritional status of our
patients. However, there were no significant differences
in nutritional status among the three groups.
We investigated the relationship between the PCr/Pi
ratio at 4 min after exercise and several variables.
The PCr/Pi ratio at 4 min after exercise did not correlate with parameters of cardiac function, Pao 2 and
Pvo 2 • These data suggested that delayed recovery of
skeletal muscle after exercise is not due to changes
in these parameters. These results might, in part,
explain the lack of correlation between parameters of
cardiac function and exercise tolerance in these
patients.
In conclusion, our data demonstrated metabolic
abnormalities in skeletal muscle of patients with CLD
and CHF which were not due to undernutrition.
These may result from reduced Cao 2 and AOO, and
be partially due to physical detraining.
Acknowledgements: The authors thank H.
Takagi for assistance in performing the exercise
studies and T. Nango for assistance in preparation
of the manuscript.
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